Since most deaths from cancer are due to metastases that are resistant to conventional therapies, understanding the fundamental tumor cell properties and host factors that control cancer metastasis and the design of new approaches to therapy are the major goals of our research program. We shall continue to develop relevant orthotopic animal models to study the biology of human cancer metastasis and isolate new nonmetastatic and organ-specific (lymph node, bone) metastatic variants from human prostate cancers. We shall investigate the molecular mechanisms for organ-specific metastasis in visceral organs and the brain. To predict the metastatic potential of individual patients' tumors, we shall develop a multiparametric assay using several molecular probes to detect upregulation (mRNA) of genes that regulate different essential steps in the pathogenesis of metastasis by human neoplasms. Since the organ environment influences tumor cell properties that include sensitivity to therapy, we shall determine the molecular mechanism by which normal tissues modulate expression of P-glycoprotein in organ-specific metastases. We shall also attempt to inhibit the in vivo induction of drug resistance in tumor cells by interfering with phosphorylation of growth factor receptors. The in vivo metastatic models developed in our laboratory are ideally suited to determine the potential of gene therapy. We plan a series of collaborations to study IRF-1 gene transfer to induce production of IFN-beta in metastatic human colon cancer cells (and, hence, decrease angiogenesis and invasiveness) and gene therapy by introducing the Herpes Simplex-tk gene ("suicide gene") into human colon and prostate cancers growing in nude mice. The biologic diversity of neoplasms implies that the successful treatment of metastasis must include a modality that circumvents the problems of heterogeneity and resistance to conventional therapies. Since macrophages activated systemically with liposomes containing synthetic immunomodulators destroy tumor cells that are resistant to conventional chemo- and biological therapies, we shall continue to study their potential for therapy of metastasis. We plan to identify potent molecule for systemic activation of macrophages and to understand on a molecular level the processes by which monocytes are rendered tumoricidal. The knowledge gained from these studies will be translated into clinical trials using liposomes/immunomodulators developed in our laboratory.